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Ifn-gamma inhibitors in the treatment of motoneuron diseases

a technology of ifn-gamma inhibitors and motoneuron diseases, which is applied in the field of treatment of motoneuron diseases, can solve the problems of preventing the development of effective therapies, unable to reverse the damage already done to motoneurons, and unable to achieve effective treatments

Inactive Publication Date: 2012-11-01
UNIV DE PROVENCE D AIX MARSEILLE I +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011](a) Providing a virion comprising a viral vector, said vector comprising at least one expression control element operably linked to a nucleic acid sequence encoding for an IFNγ antagonist; (b) Bringing the virion into contact with the said cells, whereby transduction of the viral vector results in the expression of said nucleic acid sequence in the transduced cells and the expression of said nucleic acid sequence by said cells.
[0012]A fourth aspect of the inventi

Problems solved by technology

Accumulating evidence suggests that mutant SOD1-mediated damage in glial cells contributes to ALS pathogenesis by releasing factors selectively toxic to motoneurons, but the mechanistic basis of this motoneuron-specific elimination is poorly understood, impeding therefore the development of effective therapies.
The main challenging issue regarding therapeutic approaches for motoneuron diseases concerns the delivery of therapeutic message to the broadest number of motoneurons.
However, no treatment is able to reverse the damage already done to motoneurons.

Method used

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  • Ifn-gamma inhibitors in the treatment of motoneuron diseases
  • Ifn-gamma inhibitors in the treatment of motoneuron diseases
  • Ifn-gamma inhibitors in the treatment of motoneuron diseases

Examples

Experimental program
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Effect test

example 1

IFNγ-Induced Motoneuron Death

[0110]In order to support the role of IFNγ in motoneuron death in ALS, the following preliminary tests were conducted.

In Healthy Motoneurons

[0111]IFNγ receptor chain 1 (IFNγR1) and chain 2 (IFNγR2) are expressed in nearly all Hb9::GFP motoneurons (embryonic motoneurons (E12.5) isolated from transgenic mice expressing the green fluorescent protein (GFP) under the control of the motoneuron-selective Hb9 promoter (Hb9::GFP) to facilitate motoneuron tracing) in vitro as shown by immunostaining 24 hours after seeding with antibodies directed against IFNγR1 or IFNγR2 as described below.

[0112]The exposure of motoneurons to a suboptimal dose of sLIGHT and increasing doses of IFNγ shows that IFNγ substantially enhances the LIGHT killing effect and that this synergetic lethal effect is specific to LIGHT since IFNγ had no effect on sFasL-induced death (FIG. 1B). Recombinant IFNγ induced death of about 50% of motoneurons in a dose-dependent manner (FIG. 1A). The syn...

example 2

IFNγ Levels in Serum and Cerebrospinal Fluid are Increased in ALS

[0119]The efficacy of a method for detection and / or prognosis of ALS and disease progression according to the invention are tested through the measure of IFNγ levels in serum and spinal cord of SOD1G93A mice and ALS patients, at different disease stages.

IFNγ Levels in Serum and Lumbar Spinal Cord of Sod1G93A Mice Compared to Age-Matched Wildtype and SOD1WT Mice

[0120]An enzyme-linked immunoabsorbent (ELISA) analysis was carried out to titer for IFNγ levels wherein mice of indicated genotype were bled at 13 weeks of age. Lumbar spinal cords were dissociated in 50 mM Tris-Hcl pH 7.5, 100 mM NaCl containing a cocktail of protease inhibitor (complete EDTA-free tabs, Roche Diagnostic). Spinal cord homogenates were centrifuged at 10,000×g for 10 min at +4° C. and protein concentration was determined in supernatants using Bradford assay (BioRad). Levels of IFNγ were then determined using mouse IFNγ ELISA kit II OptEIA™ (BD Bio...

example 3

Rescue from Neurotoxicity of Astrocytes by Antagonizing the IFNγ-Induced LIGHT-Triggered Death Pathway

[0134]The efficacy of a method according to the invention are tested through the therapeutic impact of the inhibition of IFNγ, by using an antagonizing antibody in vitro and in vivo. Disease progression and lifespan is determined by behavioural and histopathological analysis as described in Example 2.

Purified Motoneurons Rescued with Neutralizing Anti-IFNγ Antibodies

[0135]The potential of anti-IFNγ antibodies to protect motoneurons from death induced by recombinant mouse IFNγ was first assessed in vitro in cultured motoneurons (FIG. 5). As described in Example 1, recombinant IFNγ, or sLIGHT, or agonistic anti-LT-βR antibodies, induced death of about 50% of motoneurons. Neutralizing goat polyclonal anti-IFNγ antibodies (15027, Sigma-Alrich) efficiently blocked IFNγ- or LIGHT-induced death of cultured motoneurons. IFNγ in combination with irrelevant rat IgG did not rescue motoneurons ...

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Abstract

The present invention is directed to new compositions uses thereof and related methods for the treatment of a motoneuron disease or disorder. In particular, the invention relates to the new use of IFNγ antagonists or viral vectors, uses, compositions thereof and related methods for the treatment of motoneuron disease or disorder such as ALS.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the treatment of motoneuron diseases, in particular, amyotrophic lateral sclerosis (ALS).BACKGROUND OF THE INVENTION[0002]ALS is an incurable adult-onset neurodegenerative disease that affects primarily upper and lower motoneurons in the brain and spinal cord. Dominant mutation in superoxide dismutase-1 (Sod1) gene is the most prominent cause of inherited ALS: approximately 10% of ALS cases have a familial history of the disease and among these, 20% are caused by a dominantly inherited mutation in the superoxide dismutase-1 (SOD1) gene. Accumulating evidence suggests that mutant SOD1-mediated damage in glial cells contributes to ALS pathogenesis by releasing factors selectively toxic to motoneurons, but the mechanistic basis of this motoneuron-specific elimination is poorly understood, impeding therefore the development of effective therapies.[0003]Mice expressing human SOD1 mutations develop a motor syndrome with features...

Claims

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Application Information

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IPC IPC(8): A61K48/00A61K31/7088A61K38/21A61P25/00G01N33/566C12Q1/68C40B30/04C12N15/86C12N15/63A61K39/395
CPCA61K38/00A61K2039/505C07K2317/76C07K16/249C07K14/57A61P25/00
Inventor AZEREDO DA SILVEIRA LAJAUNIAS, SAMAREHAEBISCHER, JULIANNERAOUL, CEDRIC
Owner UNIV DE PROVENCE D AIX MARSEILLE I
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